Alcohol abuse is the most important cause of chronic pancreatitis, an inflammatory process characterized by destruction of the exocrine pancreas, fibrosis and ductular stenosis. While acute pancreatitis has been studied extensively, mechanisms responsible for chronic alcoholic pancreatitis are largely unknown in large part due to the lack of an appropriate animal model. Previous work in cultured cells and in liver has provided strong evidence for the role of free radicals in increased expression of extracellular matrix genes and subsequent increased production of type I and fibrillar collagen, the same types observed clinically in alcoholic pancreatitis. In exciting new pilot work, we have developed a unique method to collect pancreatic juice and analyze it for free radicals. After only one month of exposure of rats to enteral ethanol using the Tsukamoto-French model, clear evidence for production of a-hydroxy ethyl radical from ethanol was obtained. This occurred without evidence of tissue injury or changes in rates of collagen mRNA formation. Thus, free radical formation in the pancreas is an early event following chronic exposure to ethanol. Although the Tsukamoto-French model has been used to study alcoholic: pancreatitis; the frequency of pathology was too low to make it a useful model for mechanistic studies. Therefore, the primary goal of this research is to develop a useful model of alcoholic pancreatitis. This goal will be achieved by evaluation of three separate modifications of the Tsukamoto-French enteral ethanol delivery protocol: I) Addition of carbonyl iron to the diet; 2)chronic injection of the CCK analog, caerulein; 3) administration of an adenovirus vector expressing TGFbeta1 via the pancreatic duct. At one, two and five months after the above treatments, free radicals will be evaluated using the shin trapping technique and EPR, while pancreatic pathology will be assessed from histology, pancreatic enzymes, cellular atrophy, collagen protein and mRNA levels. Any procedure causing significant chronic elevation in enzymes 3-fold above basal with a pancreatic histology score of +2 or greater will be judged as successful. We expect these important studies to lead to the development of a new clinically relevant animal model of chronic alcoholic pancreatitis which is required for studies on mechanism and development of new therapeutic strategies.